Rothmund-Thomson syndrome (RTS) is an autosomal recessive disorder characterized by growth deficiency, skin and skeletal abnormalities, and a predisposition to cancer. Mutations in the RECQ4 gene, one of five human homologs of the E. coli recQ gene, have been identified in the majority of RTS patients. RecQ helicases are thought to play roles in regulating homologous recombination and the maintenance of genomic integrity. The RecQ4 protein has been expressed in bacteria, purified to near homogeneity, and shown to possess ssDNA-dependent ATPase activity. The goal of this fellowship project will be to characterize the RecQ4 protein both in vitro and in vivo to determine its biochemical and genetic functions. Specifically, whether RecQ4 can unwind DNA substrates that resemble recombination intermediates will be investigated, and a potential interaction of RecQ4 with human topoisomerase Ill alpha will be ascertained. In addition, a genetic approach will be pursued to define the effect of inhibition of RECQ4 expression on cell survival, cell cycle progression, DNA repair, and homologous recombination in human cells. [unreadable] [unreadable]